# Genome-wide CRISPR screen identified NEK6 as a determinant of sensitivity to CDK4/6 inhibitor in endometrial cancer

## TL;DR

A CRISPR screen found that NEK6 levels affect how well CDK4/6 inhibitors work in endometrial cancer, suggesting a new treatment strategy.

## Contribution

NEK6 is identified as a novel synthetic lethal target for CDK4/6 inhibitors in endometrial cancer.

## Key findings

- NEK6 levels determine the anti-tumor effects of CDK4/6 inhibitors in endometrial cancer.
- Combined inhibition of NEK6 and CDK4/6 suppresses tumor growth in vitro and in vivo.
- NEK6 promotes YBX1 phosphorylation and activation of CDK2 and bcl2 transcription.

## Abstract

Endometrial cancer (EC) harbors highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of CDK4/6 inhibitors in these cancers. In this study, we performed a genome-wide CRISPR-Cas9-based knockout screen to identify genes that modify the response to CDK4/6 inhibitors. We found that NIMA-related kinase-6 (NEK6) levels determine the anti-tumor effects of CDK4/6 inhibitors and that NEK6 was a synthetic lethal target of CDK4/6 inhibitors in EC. We further demonstrated that combined inhibition of NEK6 and CDK4/6 resulted in marked suppression of tumor growth in vitro and in vivo. Mechanistically, NEK6 bound to Y-box binding protein-1 (YBX1) in the cytoplasm and facilitated its phosphorylation at serine 102 (p-YBX1S102), which promoted YBX1 nuclear translocation and further activated CDK2 and bcl2 transcription. As such, these data provided robust pre-clinical mechanistic evidence of synergy between NEK6 and CDK4/6 inhibitors and delineated a path for translation of these findings to preliminary clinical studies in EC patients.